In living bodies of mammals, various prostaglandins and various leukotrienes are produced by various stimulations such as inflammatory and physical stimulations. Both of prostaglandins and leukotrienes are metabolites of arachidonic acid, and they are physiologically active substances called lipid mediators. They trigger various kinds of physiological reactions of mammals by binding to their respective receptors expressed on cell surfaces or expressed intracellularly.
Arachidonic acid is produced from phospholipids such as phosphatidylcholine as substrates, which are components of cell membranes, with the aid of the enzymatic activity of phospholipase A2 (PLA2). In particular, type 4 PLA2 is activated by inflammatory stimulation, and plays an important role in the arachidonic acid production. Arachidonic acid produced by PLA2 is converted into prostaglandin (PG) H2 by an enzymatic activity of constitutive-type cyclooxygenase (COX) 1 or inducible-type COX-2 and further converted into PGE2, PGD2, PGF2α, PGI2, thromboxane (TX) A2 and the like by each synthetic enzyme. Further, arachidonic acid is also metabolized by 5-lipoxygenase (5-LO) to give leukotriene (LT) A4, and further converted into LTB4, LTC4, LTD4, LTE4 and the like by enzymatic activities of LTA4 hydrolase, LTC4 synthase, and glutathione-5-transferase [Goodman and Gilman's the Pharmacological Basis of Therapeutics, 11th edition (Hirokawa Shoten), 2007, p. 814; C. D. Funk, SCIENCE, 2001, vol. 294, p. 1871].
Each of the prostaglandins binds with a specific receptor to cause, for example, inflammatory reactions such as fervescence, increase of blood vessel permeability, vasodilation, swelling, and pain, bronchial smooth muscle contraction, platelet aggregation, tumor cell proliferation, bone resorption promotion, nerve cell degeneration and the like, and plays an important role in expression of symptoms or formation of pathological states in various diseases. Leukotrienes are physiological substances, each of which binds with a specific receptor to cause, for example, inflammatory reactions such as excessive accumulation of leucocytes and increase of blood vessel permeability, smooth muscle contraction, mucus secretion, tumor cell proliferation and the like, and also play an important role in expression of symptoms or formation of pathological states in various diseases.
Although inflammatory reactions, per se, are essential reactions in order that living bodies can survive when they face a pathogenic substance or affection, inflammatory reactions sometimes occur in excess levels in certain conditions or diseases, or they may sometimes continue without any reason for bringing evident benefits [Goodman and Gilman's the Pharmacological Basis of Therapeutics, 11th edition (Hirokawa Shoten), 2007, p. 837]. Conditions of living bodies exhibiting acute or chronic inflammatory reactions referred to in the present specification mean conditions where excess or non-profitable inflammatory reactions are generated acutely and transiently or chronically and continuously. Further, inflammatory reactions are a series of events caused by stimulations including physical hazards such as those caused by heat, infectious substance, ischemia, antigen-antibody reaction and the like, and they are accompanied by flare, swelling, algesia, and pain generation as well-known macroscopic clinical symptoms. As histological mechanisms of these symptoms, it is known that vasodilation, increase of blood vessel permeability, invasion of leucocytes and phagocytes, decomposition or fibrosis of tissues and the like are caused [Goodman and Gilman's the Pharmacological Basis of Therapeutics, 11th edition (Hirokawa Shoten), 2007, p. 837]. It is known that many of these histological reactions are triggered by prostaglandins and/or leukotrienes, and prostaglandins and/or leukotrienes have important roles in the inflammatory reactions.
For example, in a pathological tissue of rheumatoid arthritis, which is an autoimmune disease and is one of chronic inflammatory diseases, expression of COX-2 and production of PGE2 or TXA2 as well as expression of 5-LO and production of LTB4 are observed [Bonnet et al., Prostaglandins, 1995, vol. 50, p. 127]. In a mouse deficient in FLAP which is a protein required for activation of 5-LO, symptoms of collagen-induced arthritis, as a disease model of chronic rheumatoid arthritis, are reported to be milder compared with those in a wild-type mouse [Griffiths et al., J. Exp. Med, 1997, vol. 185, p. 1123]. Thus, prostaglandins and leukotrienes are demonstrated to be responsible for important roles in the formation of pathologies of chronic rheumatoid arthritis.
In a pathological tissue of bronchial asthma, which is one of chronic allergic diseases, overproduction of PGD2 and TXA2 as well as overproduction of LTC4 and LTD4 are observed [Wenzel et al., Am. Rev. Respir. Dis, 1990, vol. 142, p. 112], and airway hypersensitivity, which is a disease model of bronchial asthma, is reported to unlikely occur in a PGD2 receptor deficient mouse [Matsuoka et al., SCIENCE, 2000, vol. 287, p. 2013]. Accordingly, roles of prostaglandins and leukotrienes are demonstrated to be important in bronchial asthma.
In a cerebral tissue after ischemia and reperfusion, expression of COX-2 is increased to increase PGE2 and TXA2 concentrations, whereas activity of 5-LO is increased to increase production of LTC4 [Ohtsuki et al., Am. J. Physiol., 1995, vol. 268, p. 1249]. Thus, it is known that prostaglandins and leukotrienes are responsible for important roles in the formation of infarct, which is recognized as a disorder from ischemia and reperfusion. In a pathological tissue of Alzheimer's disease, which is one of diseases accompanied by neurodegeneration, it is demonstrated that COX activity and 5-LO activity are increased, and prostaglandins and leukotrienes cause formation of β-amyloid proteins which constitute one class of pathogenic substances of Alzheimer's disease to induce degeneration of nerve cells [Sugaya et al., Jpn. J. Pharmacol., 2000, vol. 82, p. 85]. Thus, it is considered that prostaglandins and leukotrienes are responsible for important roles in formation of neurodegenerative diseases such as Alzheimer's disease.
In a pathological tissue of colon cancer, for example, COX and 5-LO are expressed, and the production of prostaglandins and leukotrienes are increased [Dreyling et al., Biochim. Biophys. Acta, 1986, vol. 878, p. 184]. Further, leukotrienes are reported to cause proliferation of colon cancer cells [Qiao et al., Biochim. Biophys. Acta, 1995, vol. 1258, p. 215; Hong et al., Cancer Res., 1999, vol. 59, p. 2223]. Thus, it is considered that prostaglandins and leukotrienes also play important roles in tissues of colon cancer.
Involvements of prostaglandins and/or leukotrienes in diseases and pathological conditions are not limited to the diseases exemplified above. It has been demonstrated that prostaglandins and/or leukotrienes are involved in various conditions, diseases, and pathological states accompanied by acute or chronic inflammatory reactions, and that their roles are important. From the above facts, various kinds of inhibitors against prostaglandin production or against leukotriene production have been used as agents for prophylactic or therapeutic treatment of conditions, diseases, and pathological conditions with acute or chronic inflammatory reactions.
Drugs having suppressing actions on prostaglandin production include various kinds of non-steroidal anti-inflammatory drugs (NSAIDS), and they have been used as agents for therapeutic treatment of chronic rheumatoid arthritis and osteoarthritis, anti-inflammatory analgesics for external injury and the like, agents for prophylactic treatment of cerebral infarction or myocardial infarction, agents for prophylactic treatment of colorectal polyposis and the like. However, various kinds of NSAIDS inhibit only the production of prostaglandins, and as a result, they increase production of leukotrienes to cause side effects such as asthmatic attack and gastrointestinal injury, and in addition, exhibit side effects of nephropathy and the like. Further, differences in an effective dose and a dose inducing the side effects are small in these NSAIDS, and no satisfactory drug is available also from a viewpoint of a therapeutic effect. For example, it has been reported that inhibition of COX by the above drug leads to suppression of biosynthesis of PG required for maintaining homeostatic functions in the upper gastrointestinal tract such as stomach and duodenum, kidney, and the like, and as a result, for example, they induce side effects such as upper gastrointestinal injury and/or renal dysfunction [Goodman and Gilman's the Pharmacological Basis of Therapeutics, 11th edition (Hirokawa Shoten), 2007, Chapter 26].
5-LO inhibitors described in EP279263 are available as drugs having suppressing action on leukotriene production and are known as prophylactic agents for asthma. However, their doses are limited because of induction of side effects such as hepatotoxicity, which results in unsatisfactoriness from a viewpoint of a therapeutic effect. Steroids inhibit productions of both of prostaglandins and leukotrienes, and accordingly, they are used as prophylactic or therapeutic agents for treatment of conditions of living bodies, various diseases, or pathological states with various acute or chronic inflammatory reactions. However, their actions are not limited to the suppressing action on lipid mediator production, but they have severe side effects such as induction and exacerbation of infection due to immune suppressing effects, growth delay and dermatrophy due to suppressing action on normal cell proliferation, digestive ulcer and the like. Therefore, their use has been limited.
Under the circumstances as explained above, a compound which suppresses production of both of prostaglandins and leukotrienes and shows less side effects is considered to be effective as a therapeutic or prophylactic agent for the conditions, diseases or pathological states of living bodies in mammals as described above, and a method of using such compound and an existing medicament in combination is considered to be a further effective method for therapeutic treatment or prophylactic treatment. Therefore, it is desired to create a compound which suppresses production of both of prostaglandins and leukotrienes and to develop the compound as a medicament.
Although the compounds disclosed in Patent documents 1 to 3, for example, are known as compounds exhibiting the same affect as that of the compounds of the present invention, all of these compounds are structurally different from the compounds of the present invention.
Patent document 1: International Patent Publication WO99/19291
Patent document 2: International Patent Publication WO03/07686
Patent document 3: International Patent Publication WO05/016862